This invention relates to ultrasonography and, more particularly, to medical techniques which employ ultrasonography. Specifically, the invention is directed to the use of ultrasonic imaging for assigning the anatomic sex of a human fetus during early pregnancy, that is, in the period between the twelfth week and the fourteenth week of gestation.
Technological progress continues to improve the spatial resolution of images obtained using linear-array real-time ultrasound in obstetrical genetics. The change from analog to digital ultrasound systems has contributed to this improvement. With the improvement in resolution in digital linear-array real-time ultrasound systems has come marked improvement in identification of specific parts of fetal anatomy at an increasingly earlier stage of gestation.
The use of ultrasound, or high-frequency sound waves, to produce an image on a screen of a developing fetus and surrounding tissues has increased dramatically in recent years, not only in hospitals, but in doctors' offices. A panel recently convened by the National Institutes of Health concluded that there are more than two dozen medical reasons which warrant the use of ultrasound scans in some cases, including the detection of abnormalities in a fetus, when a doctor has evidence that a medical problem exists; the detection of the presence of twins; the collection of information for the evaluation of fetal growth, activity, and position; and the determination of fetal age for better management of the pregnancy. National Institutes of Health, Consensus Development Conference Consensus Statement, "The Use of Diagnostic Ultrasound Imaging in Pregnancy," Feb. 6-8, 1984.
Heretofore, ultrasound has been used in the area of prenatal medical diagnosis primarily to assess the gestational age, the location of the fetus, and the location of the placenta (afterbirth) in association with the performance of genetic amniocentesis by needle aspiration of amniotic fluid. More recently, it has been used to detect fetal deformities and other structural genetic problems. Ultrasound scans have been used, for example, to ascertain whether or not a fetus is growing properly according to measurement milestones. It has been possible to identify the fetus with a structural defect of growth by assessing limb development, thereby diagnosing short limb dwarfism syndromes, such as prenatal diagnosis of lethal osteogenesis imperfecta.
Knowing the fetus' sex, however, can also be important if a family has a history of genetic disease linked to the X chromosome, which along with the Y chromosome determines sex. Genetic diseases, such as hemophilia A (a bleeding disorder), chronic granulomatous disease, and Lesch-Nyhan disease, that only affect males, are linked to the X chromosome. If a family has a history of the disease, it is desirable to ascertain whether the fetus is a male or a female. In the case of a male fetus, further studies can be performed to determine whether or not the fetus possesses the gene that causes the disorder, such as hemophilia A, for example.
In the case of X-linked disorders, some of which can be prenatally diagnosed by chemical tests but others of which cannot yet be diagnosed, being able to identify the sex of the fetus also has important consequences in terms of the patient interview interaction called genetic counseling. The ability to identify the fetus developing as a female, which cannot be affected even if it is carrying the gene for the disorder, provides the mother with the information she needs to feel reassured with continuation of the pregnancy knowing that she will not bear an affected infant.
Generally, a fetus' sex has heretofore been determined by the in vitro technique known as genetic amniocentesis. Genetic amniocentesis requires the removal of fetal cells from the fluid that surrounds the fetus and cannot safely be performed before the sixteenth week of gestation. Genetic amniocentesis can only be achieved by inserting a large bore (20-22 gauge) needle through the mother's abdomen to withdraw fetal cells. It is known to be associated with an incidence of spontaneous abortion in about one procedure in every 200 cases.
In view of the risks to the mother and the fetus posed by the invasive procedure required by genetic amniocentesis and in light of the aforementioned advances in digital linear-array real-time ultrasound systems, various researchers have investigated the use of ultrasonography in determining fetal sex. Several researchers have published results of sex determination using ultrasound, generally in the developmental stages of pregnancy beyond the fourteenth week. See, for example, Stocker, J., and Evans, L., "Fetal Sex Determination by Ultrasound," Obstet, Gynecol. 50:462 (1977); Conti, M., Plicchi, G., and Altobelli, L., "Accurate Sexing With the Aid of the Real Time Ultrasonography," IRCS Med. Sci. 7:108 (1979); Le Lann, D., Schioceht, F., Heintz, M., et al., "Antenatal Diagnosis of the Sex of the Fetus by Diagnostic Ultrasound (Echograpohy)," J. Gynecol. Obstet. Biol. Reprod. (Paris) 8:315 (1979); DeLaFuente P Olaizola J. I., Iglesias, E., et al., "Diagnosis of the Fetal Sex by Ultrasonography," Clin. Invest. Gynecol. Obstet. 6:223 (1979); Shalev, E., Weiner E. Zuckerman H. "Ultrasound Determination of Fetal Sex," Am J Obstet. Gynecol. 5:141, 582-583 (Nov. 1, 1981); and Dunne, M. L., Cunat, J. S., "Sonographic Determination of Fetal Gender Before 25 Weeks Gestational Age," A. J. R. 140:741-743 (1983).
In the reports of fetal sex determination by ultrasound, the accuracy reported has not been impressive. Determination of female sex has been performed by exclusion of male sex. Furthermore, the earliest time for accurate determination of sex has been reported as being the twenty-sixth week of gestation, thus precluding clinical use of this technique for diagnosis of recessive X-linked disorders. In one report of 227 mothers examined during and after the twentieth week of pregnancy, fetal sex was determined only in 44 percent of the cases with an 87 percent accuracy rate. In a further report on 381 mothers in whom an attempt was made to determine fetal sex in all gestations at or beyond the twentieth week, an accuracy of 100 percent was obtained for fetuses designated as male and confirmed as male at delivery. However, the accuracy of determination of female sex was 97 percent. Shalev, E., Weiner, E., Zuckerman, H., "Ultrasound Determination of Fetal Sex," Am. J. Obstet. Gynecol. 5:141, 582-583 (1981).
A recent report of fetal sex determination by ultrasound indicates improvement both in accuracy and at earlier stages of gestation. Dr. Jason C. Birnholz, however, achieved only 69 percent accuracy in determining the sex of 855 fetuses after 15 weeks of pregnancy, which he believed could be imaged well enough with ultrasound for sex to be determined. That is, the determination of sex by Birnholz required that an ultrasonic image of the fetal external genitalia appear in a mature stage of development (i.e., that the fetal external genitalia could be visualized as being fully formed) before sex was assigned. Birnholz, J. C., "Determination of Fetal Sex," N. Engl. J. Med. 309:942-944 (1983), and Larry Thompson, "Technique Shows Sex of Fetus at 14 Weeks," San Jose Mercury News, Thursday, Oct. 20, 1983, pages 1A, 9A. Natsuyama, E., "Sonographic Determination of Fetal Sex From Twelve Weeks of Gestation," Am. J. Obstet. Gynecol. 7:149, 748-757 (Aug. 1, 1984), purports to show accurate fetal sexing from 12 to 40 weeks of gestation. However, the accuracy in early pregnancy from 12 to 14 weeks was only as high as about 85 percent. Only by the demonstration of 100 percent accuracy within an early prenatal diagnosis gestational age range can consideration be given to the technique of fetal anatomic sex assignment by ultrasonography becoming complementary to, and in selected situations serve as a replacement for, genetic amniocentesis for fetal sex determination.